Appropriate regulation of cellular metabolic processes involved in ATP-generation is necessary for normal tissue development and homeostasis. The capacity for cellular ATP generation is regulated by developmental, physiological, and environmental cues requiring transducing events from the cell surface to the nucleus. The transcriptional coactivator, PPARgamma Coactivator 1 (PGC-1), is an excellent candidate for transducing signals to genes involved in cellular energy production. PGC-1alpha displays a unique tissue-specific and developmental expression profile and is inducible by environmental stimuli, such as cold exposure, fasting, and exercise. Through its function as a transcriptional coactivator, PGC-1alpha regulates a wide array of cellular metabolic processes, including mitochondrial oxidative pathways in heart, skeletal muscle, and brown adipose; and gluconeogenesis in liver. PGC-1alpha coactivates a number of transcription factors, most notably members of the nuclear receptor superfamily. PGC-1alpha expression is altered in pathologic states, such as diabetes mellitus and cardiac hypertrophy, and PGC-1a polymorphisms have been linked to increased risk of diabetes mellitus in humans. Recently, we have identified the nuclear orphan receptor, estrogen-related receptor a (ERRalpha), as a novel PGC-1alpha partner. This proposal is designed to test the hypotheses that PGC-1alpha functions a bona fide coactivator for ERRalpha and its related isoform, ERRgamma; and that the ERRs mediate distinct metabolic regulatory effects of PGC-1alpha in response to physiologic stimuli. To demonstrate that PGC-1a is an ERR coactivator, functional and structural features of the PGC-1alpha/ERR interaction will be characterized using transcriptional assays in cell culture and in vitro binding studies. The role of ERR isoforms in mediating downstream metabolic effects of PGC-1alpha will be determined by characterizing the metabolic phenotypes in both loss-of-function (ERRa null mice) and a gain-of-function (adenoviral overexpression of ERR isoforms in cells) models. The long-term goal of this project is to define the role of PGC-1alpha/ERR in the control of a subset of cellular metabolic homeostatic responses relevant to physiologic and pathologic processes in muscle and adipose tissue.